Traditional linkage analysis in admixed families

Currently there is no general method to study the impact of population admixture within families on the assumptions of random mating and consequently, Hardy-Weinberg equilibrium (HWE) and linkage equilibrium (LE) and on the inference obtained from traditional linkage analysis. ^ First, through simulation, the effect of admixture of two populations on the log of the odds (LOD) score was assessed, using Prostate Cancer as the typical disease model. Comparisons between simulated mixed and homogeneous families were performed. LOD scores under both models of admixture (within families and within a data set of homogeneous families) were closest to the homogeneous family scores of the population having the highest mixing proportion. Random sampling of families or ascertainment of families with disease affection status did not affect this observation, nor did the mode of inheritance (dominant/recessive) or sample size. ^ Second, after establishing the effect of admixture on the LOD score and inference for linkage, the presence of induced disequilibria by population admixture within families was studied and an adjustment procedure was developed. The adjustment did not force all disequilibria to disappear but because the families were adjusted for the population admixture, those replicates where the disequilibria exist are no longer affected by the disequilibria in terms of maximization for linkage. Furthermore, the adjustment was able to exclude uninformative families or families that had such a high departure from HWE and/or LE that their LOD scores were not reliable. ^ Together these observations imply that the presence of families of mixed population ancestry impacts linkage analysis in terms of the LOD score and the estimate of the recombination fraction. ^

Land Inheritance Rules: Theory and Cross-Cultural Analysis

This paper develops a general theory of land inheritance rules. We distinguish between two classes of rules: those that allow a testator discretion in disposing of his land (like a best-qualified rule), and those that constrain his choice (like primogeniture). The primary benefit of the latter is to prevent rent seeking by heirs, but the cost is that testators cannot make use of information about the relative abilities of his heirs to manage the land. We also account for the impact of scale economies in land use. We conclude by offering some empirical tests of the model using a cross-cultural sample of societies.

Parental demographic risk factors and occupational exposure to ionizing radiation for achondroplasia, thanatophoric and autosomal deletions in Texas, 1996--2002

Little is known about the etiology of Achondroplasia (AC), Thanatophoric Dwarfism (TD), and autosomal deletions (CD). These syndromes are due to fully penetrate genetic mutations, yet arise de novo, instead of being inherited. We examined the association between parental demographic characteristics and parental occupations with exposure to ionizing radiation and these birth defects. ^ We conducted a cross-sectional study and two case-control studies using a large database that was created by linking records from Texas Birth Defects Registry, Texas birth certificates and Texas fetal death certificates from 1996 to 2002. The first case-control study was matched on paternal age and examined 73 cases of AC and 43 cases of TD. The second case-control study was unmatched and examined 343 cases of autosomal deletion syndromes. ^ We used a job exposure matrix (JEM) to measure exposures to ionizing radiation in the workplace. This gives an estimate of the intensity and probability of exposure to ionizing radiation for each occupation and industry. ^ The prevalence rate of Achondroplasia, Thanatophoric Dwarfism and autosomal deletions was 0.36 per 10,000, 0.21 per 10,000, and 1.68 per 10,000 births respectively in Texas 1996–2002. ^ Older fathers had a strong increase in the risk of having offspring with AC or TD and a modest increase in the risk of CD. Fathers who were Black or Hispanic were less likely to have infants with AC or TD compared to Whites (adjusted POR=0.61; 95% CI 0.30, 1.26 and 0.44; 95% CI 0.27, 0.88, respectively). Black fathers and Hispanic mothers were also less likely to have infants with CD (adjusted POR=0.54; 95% CI 0.22, 1.35 and 0.62; 95% CI 0.39, 0.97). ^ After adjusting for other parental demographic factors, there was no significant relation between fathers exposure to ionizing radiation in the work place and AC or TD (adjusted OR=0.48; 95% CI 0.19, 1.25) and no significant relation between parental exposure to ionizing radiation in the work place and CD (adjusted OR=1.16; 95% CI 0.73, 1.85). ^ This is the first study to find an association between father's age and TD and CD and paternal race and AC or CD. Parental exposure to radiation for therapeutic or diagnostic indications was not measured, thus it can not be excluded as a cause of these birth defects. ^

Genetic variants within the Wnt/ B-catenin signaling pathway as indicators of bladder cancer clinical outcomes

The genetic factors that influence bladder cancer clinical outcomes are largely unknown. In this clinical outcomes study, I assessed genetic variations in the Wnt/β-catenin stem-cell pathway genes for association with recurrence and progression. A total of 230 SNPS in 40 genes from the Wnt/β-catenin pathway were genotyped in 419 histologically confirmed non-muscle invasive bladder cancer cases. Several significant associations were observed in the clinical outcomes analysis. Under the dominant model WNT8B: rs4919464 (HR: 1.55, 95% CI: 1.17-2.06, P=2.2x10-3) and WNT8B: rs3793771 (HR: 1.54, 95% CI: 1.09-1.62, P=4.6x10-3 ) were statistically significantly associated with an increase risk of recurrence while two other variants, APC2: rs11668593 (HR: 2.50, 95% CI: 1.43-4.35, P=1.2x10-3) and LRP5 : rs312778 (HR: 1.81, 95% CI: 1.23-2.65, P=2.7x10-3), were significantly associated with recurrence risk under the recessive model of inheritance. Four SNPs in the recessive model were associated with an increased risk of progression (AXIN2: rs1544427, LRP5: rs312778, AXIN1: rs370681, AXIN1: rs2301522). LRP5: rs312778 had the most significant increased risk of progression with a 2.68 (95% CI: 1.52-4.72, P=6.4x10-4)-fold increased risk. Stratification analysis based on treatment regimen (transurethral resection (TUR) and Bacillus Calmette-Guérin (BCG)) was also performed. Individuals with at least one variant in AXIN2: rs2007085 were found to have a 2.09 (95% CI: 1.24-3.52, P=5.4x10-3) -fold increased risk of recurrence in those that received TUR only, and no statistically significant effect was seen in those that received BCG. Individuals who received TUR with at least one variant in LEF1: rs10516550 were found to have a 2.26 (95% CI: 1.22-4.18, P=9.7x10-3)-fold increase risk of recurrence and no statistically significant effect was found in individuals who received BCG. Also, the recessive model of LRP6: rs2302684 in TUR only treatment was shown to have a 1.95 (95%CI: 1.18-3.21, P=8.8x10 -3)-fold increased risk of recurrence, and a suggested protective effect associated with a (HR: 0.83, 95% CI: 0.51-1.37, P=0.468) decreased risk of recurrence. Together, these findings implicate the Wnt/β-catenin stem-cell pathway as playing a role in bladder cancer clinical outcomes and have important implications for personalization of future treatment regimens. ^

Creation of a retinoblastoma mutant with dominant -negative activity

The Retinoblastoma tumor suppressor gene (RB) plays a role in a variety of human cancers. Experimental analyses have indicated that the protein product of the RB gene (pRb) plays a role in cell cycle regulation, and that this protein is required in cellular differentiation, senescence, and cell survival. pRb function is dependent on its ability to bind to cellular factors. There are multiple protein binding domains within pRb. Mutations within these domains which eliminate the ability of pRb to bind its targets result in loss of function. Loss of pRb function leads to tumorigenesis, although uncontrolled cellular proliferation is not a universal response to pRb inactivation. The ultimate response to the loss of pRb is influenced by both the genetic and epigenetic environments. Targeted disruption of RB in mice results in embryonic lethality, demonstrating the requirement for functional pRb in development. Close examination of various tissues from the embryos which lack wildtype RB shows problems in differentiation as well as showing induction of apoptosis. Although disruption of RB has provided useful information, complete inactivation of a gene precludes the possibility of discovering the functions that separate domains may have within the system. Creation of a dominant negative mutant by domain deletion whose phenotype is expressed in the presence of the wildtype may provide information about the intermediate functions of the protein. In addition, tissue specific targeting of a dominant negative mutant of pRb allows for comprehensive analysis of pRb function in organogenesis. In this thesis, a series of RB deletion mutants were created and tested for dominant negative activity as well as cellular localization. A tissue culture assay for dominant negative activity was developed which screens for the phenotype of apoptosis due to loss of pRb function. Two mutants from this series scored positive for dominant negative activity in this assay. The effect of these mutants within the assay environment can be explained by a model in which pRb acts as a facilitator of cell fate pathway decisions. ^

Pigment concentrations and biomass of phytoplankton and of its dominant species in surface Black Sea waters in 1998-2000

Data on chlorophyll a concentration and species composition and biomass of phytoplankton have been collected for two years continues monitoring in the central part and the slope zone of the Black Sea. Seasonal dynamics of chlorophyll a concentration correspond to U-type. It is characterized by low values in summer, high values in autumn, which are going to winter-spring bloom of phytoplankton. Oscillations of mean values of chlorophyll concentrations are equal to 3-4 in the central part and 2 - in the slope zone. In the autumn-winter-spring period high values of phytoplankton biomass are related to typical blooming diatom algae in the first year and other taxons - in the second year. Relationship between relative content of phaeopigment and chlorophyll concentration has been determined for the central western part of the sea. Seasonal dynamics of carbon/chlorophyll a ratio has been shown. For both regions mean values of this ratio were equal to ~20 in autumn-winter-spring time and 40-50 - in summer time.